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REVIEW ARTICLE
Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy:Mechanisms, Clinical Implications and Knowledge Gaps
Ruben van der Galien1• Rob ter Heine1
• Rick Greupink2• Stein J. Schalkwijk1,2
•
Antonius E. van Herwaarden3• Angela Colbers1
• David M. Burger1
Published online: 19 June 2018
� The Author(s) 2018
Abstract Prevention of mother-to-child transmission of
HIV and optimal maternal treatment are the most important
goals of antiretroviral therapy in pregnant women with
HIV. These goals may be at risk due to possible reduced
exposure during pregnancy caused by physiological chan-
ges. Limited information is available on the impact of these
physiological changes. This is especially true for HIV-in-
tegrase inhibitors, a relatively new class of drugs, recom-
mended first-line agents and hence used by a large
proportion of HIV-infected patients. Therefore, the objec-
tive of this review is to provide a detailed overview of the
pharmacokinetics of HIV-integrase inhibitors in preg-
nancy. Second, this review defines potential causes for the
change in pharmacokinetics of HIV-integrase inhibitors
during pregnancy. Despite increased clearance, for ralte-
gravir 400 mg twice daily and dolutegravir 50 mg once
daily, exposure during pregnancy seems adequate; how-
ever, for elvitegravir, the proposed minimal effective
concentration is not reached during pregnancy. Lower
exposure to these drugs may be caused by increased hor-
mone levels and, subsequently, enhanced drug metabolism
during pregnancy. The pharmacokinetics of bictegravir and
cabotegravir, which are under development, have not yet
been evaluated in pregnant women. New studies need to
prospectively assess whether adequate exposure is reached
in pregnant women using these new HIV-integrase inhi-
bitors. To further optimize antiretroviral treatment in
pregnant women, studies need to unravel the underlying
mechanisms behind the changes in the pharmacokinetics of
HIV-integrase inhibitors during pregnancy. More knowl-
edge on altered pharmacokinetics during pregnancy and the
underlying mechanisms contribute to the development of
effective and safe antiretroviral therapy for HIV-infected
pregnant women.
Key Points
Pregnancy leads to a reduction in pharmacokinetic
exposure to HIV-integrase inhibitors, which may
endanger viral suppression. Not all mechanisms
behind the changes in the pharmacokinetics of HIV-
integrase inhibitors during pregnancy are known and
we need to unravel these to optimize antiretroviral
therapy during pregnancy.
More knowledge on the changes in the
pharmacokinetics of HIV-integrase inhibitors during
pregnancy may further facilitate and guide the
development of effective and safe treatment of HIV-
infected pregnant women.
& David M. Burger
David.Burger@radboudumc.nl
1 Department of Pharmacy, Radboud Institute of Health
Sciences, Radboud University Medical Center, Geert
Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
2 Department of Pharmacology and Toxicology, Radboud
Institute of Molecular Life Sciences, Radboud University
Medical Center, Nijmegen, The Netherlands
3 Department of Laboratory Medicine, Radboud Institute of
Molecular Life Sciences, Radboud University Medical
Center, Nijmegen, The Netherlands
Clin Pharmacokinet (2019) 58:309–323
https://doi.org/10.1007/s40262-018-0684-z
1 Introduction
Physiological changes occurring during pregnancy affect
exposure to drugs. In particular, for newly developed
antiretroviral drugs such as HIV-integrase inhibitors,
knowledge gaps exist on the clinical relevance of the
altered pharmacokinetics, and also which physiological
changes mainly drive the altered exposure of HIV-inte-
grase inhibitors. HIV-integrase inhibitors have achieved
high rates of virologic suppression, as shown in large
clinical trials and in clinical practice, and often have
greater tolerability than protease inhibitor (PI)- or non-
nucleoside reverse-transcriptase inhibitor (NNRTI)-based
regimens [1, 2]. This led to the Department of Health and
Human Services (DHHS) guidelines recommending HIV-
integrase inhibitor-based regimens as initial therapy for
most people with HIV, over NNRTI or PI regimens [2], and
explains the large proportion of HIV-infected patients
using these agents [3–6]. The HIV-integrase inhibitors
raltegravir, dolutegravir and elvitegravir, the latter boosted
with cobicistat, have been approved in the Western world,
while the newest agents cabotegravir and bictegravir are
currently under clinical development. Because of accu-
mulating experience, as well as knowledge on efficacy,
pharmacokinetics and safety, raltegravir has become the
first-line therapy for treating HIV-infected pregnant women
in the developed world [7]. Dolutegravir is now classified
as an alternative agent for antiretroviral-naive pregnant
women, based on increasing experience, while elvitegravir
is not recommended by perinatal guidelines [7]. More
knowledge on safety, efficacy and pharmacokinetics in
pregnancy may facilitate integrase inhibitors to become
first-line therapy in HIV-endemic regions [8], and is
therefore of utmost importance.
Pregnancy may alter the pharmacokinetics of antiretro-
viral drugs [9–12]. The absorption of drugs can be changed
because of increased gastric pH or reduced intestinal
motility [13]. Several hemodynamic changes may result in
augmented plasma volume and changed tissue perfusion
[14], which can influence the volume of distribution and
clearance of drugs. Serum protein concentrations may
change during pregnancy, which may have consequences
for the protein unbound (free) fraction of drugs [15].
Lastly, increased hormone levels during pregnancy may
change the expression of metabolizing enzymes, such as
UDP-glucuronosyltransferase 1A1 (UGT1A1) [16–18] and
cytochrome P450 (CYP) 3A4 [19–22]. Induction of these
isoenzymes may lead to increased apparent clearance (CL/
F) and hence a change in exposure to HIV-integrase
inhibitors.
In this review, we provide a detailed overview of the
pharmacokinetics and potential causes for alterations in the
pharmacokinetics of HIV-integrase inhibitors during
pregnancy.
2 Methods
For each individual HIV-integrase inhibitor, we discuss the
impact of pregnancy on the following pharmacological
principles: absorption, distribution, protein binding, and
metabolism and clearance.
PubMed searches were performed using the following
search terms: ‘Raltegravir OR Isentress’ OR ‘Elvitegravir
OR Cobicistat OR GS-9137 OR GS-9350 OR Stribild OR
Genvoya’ OR ‘Dolutegravir OR Tivicay OR Triumeq OR
GSK1349572’ OR ‘Cabotegravir OR GSK1265744’ OR
‘Bictegravir OR GS-9883’ in combination with ‘Clearance’
OR ‘Distribution’ OR ‘Absorption’ OR ‘Protein binding’
OR ‘Pharmacokinetics’ OR ‘Pregnancy’ OR ‘Bioavail-
ability’ OR ‘Availability’ OR ‘Metabolism’ OR ‘Cy-
tochrome p450 enzyme’ OR ‘UGT enzyme’ OR ‘P-
glycoprotein transporter’ OR ‘Breast Cancer Resistance
Protein’. Registration information from the European
Medicines Agency (EMA) and the US FDA was used,
studies reported in ClinicalTrials.gov were screened, and
abstracts of relevant international conferences (Conference
on Retroviruses and Opportunistic Infections, International
Workshop on Clinical Pharmacology of Antiviral Therapy,
European AIDS Conference) were also screened.
Renal dysfunction and hepatic impairment are two dis-
ease states notorious for decreased plasma protein con-
centrations [23, 24]; therefore, regulatory agencies advise
to assess the unbound pharmacokinetics in plasma in
populations with these organ impairments [25–27]. In case
data on protein binding were not available in pregnancy,
we took clues from other populations with similar
decreased serum protein concentrations as pregnant women
to estimate the effect of changes in unbound concentration
of HIV-integrase inhibitors during pregnancy [28–32].
Results from studies in moderate hepatic [29–31] and
severely renally impaired patients [28] can then be useful.
However, protein binding may also be decreased due to the
accumulation of endogenous compounds, such as bilirubin,
in patients with hepatic impairment [33]. In renal impair-
ment, protein binding may be decreased due to displace-
ment by uremic toxins [34]. Therefore, these studies
[28–31] are indicative, but not necessarily representative,
for changed protein binding in HIV-infected pregnant
women.
310 R. Galien et al.
3 Results
An overview of the available HIV-integrase inhibitors and
their doses, routes of administration and current status in
pregnancy according to the DHHS guidelines [7] is pre-
sented in Table 1. Table 2 presents the current main
pharmacokinetic parameters observed in pregnancy for the
different HIV-integrase inhibitors, and Table 3 provides an
overview of the hypothetical mechanisms of changed drug
metabolism and disposition during pregnancy in relation to
the pharmacokinetics of HIV-integrase inhibitors.
3.1 Raltegravir
The pharmacokinetics of raltegravir 400 mg twice daily in
pregnant women have been described by Blonk et al. [9]
(n = 21 patients in the third trimester, and n = 18 patients
postpartum) and Watts et al. [10] (n = 16 patients in the
second trimester, n = 41 patients in the third trimester, and
n = 38 patients postpartum).
3.1.1 Absorption
Raltegravir is a P-glycoprotein (P-gp) substrate, and
increased expression of intestinal P-gp during pregnancy
could lead to reduced absorption of raltegravir [35, 36],
whereas the increased gastric pH might enhance absorption
[37]. Time to reach maximum concentration (Tmax) showed
high intersubject variability but was not different from Tmax
observed in non-pregnant, HIV-infected patients [9, 10].
Therefore, it is probable that pregnancy does not delay the
absorption of raltegravir. Maximum concentration (Cmax)
values in the second and third trimesters were slightly
lower during pregnancy but the variability was large,
resulting in overlapping confidence intervals (CIs) when
comparing third trimester values with postpartum Cmax (see
Table 2) [9, 10]. Similar high variability in Cmax has been
observed in non-pregnant patients: mean Cmax 2.17 mg/L
[38]. Blonk et al. found a 28% lower Cmax (with 90% CI of
0.55–1.23) in the third trimester than postpartum [9],
whereas Watts et al. found a 26 and 41% lower Cmax in the
second and third trimesters, respectively. Pregnancy does
not seem to influence the surrogate rate of the absorption
parameters Tmax and Cmax.
3.1.2 Distribution
In the study by Watts et al. [10], the apparent volume of
distribution (V/F) of raltegravir was shown to be increased
during the second (10.6%) and third trimesters (37.9%)
compared with postpartum. Furthermore, in the study by
Blonk et al. [9], V/F was also increased by 51.7% in the
third trimester versus postpartum. These findings suggest
that pregnancy may lead to an increased V/F of raltegravir,
possibly due to increased volume in pregnancy or
decreased bioavailability.
Table 1 Overview of available HIV-integrase inhibitors and their doses, routes of administration and current status in pregnancy, according to
DHHS guidelines
HIV-integrase inhibitor Available dose and frequency Route of
administration
Status in pregnancy according to
current DHHS guidelines
Raltegravir (Isentress) 1. 400 mg bid
2. 1200 mg—two tablets of 600 mg qd
1. Oral
2. Oral
1. First-line treatment
2. Not mentioned in the
guidelines
1. Elvitegravir/cobicistat/emtricitabine/
tenofovir disoproxil fumarate (Stribild)
2. Elvitegravir/cobicistat/emtritabine/
tenofovir/alafenamide (Genvoya)
1. 150/150/200/300 mg qd
2. 150/150/200/10 mg qd
1. Oral
2. Oral
Not recommended
1. Dolutegravir (Tivicay)
2. Dolutegravir/abacavir/lamivudine
(Triumeq)
1. 50 mg qd or bid (in case of HIV-integrase
resistance or use of co-medication)
2. 50/600/300 mg qd
1. Oral
2. Oral
Alternative treatment (qd and
bid)
1. Cabotegravir induction period ?
abacavir/lamivudine
2. Cabotegravir long-acting ? rilpivirine
(RPV)
1. 30 mg qd ? 600/300 mg qd (phase III)
2. 400 mg cabotegravir and 600 mg
rilpivirine on a monthly basis
1. Oral
2. IM
Not available
Bictegravir/emtricitabine/tenofovir
alafenamide
50/200/25 mg qd (phase III) Oral Not available
Reference DHHS prenatal guidelines [7]
bid twice daily, qd once daily, DHHS Department of Health and Human Services, IM intramuscular
Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy 311
Ta
ble
2Overview
pharmacokineticsofHIV
-integrase
inhibitors
inpregnancy
andpostpartum
Reference
Cmax(m
g/L)
CL/F
(L/h)
t �(h)
Second
trim
ester
Third
trim
ester
Postpartum
Second
trim
ester
Thirdtrim
ester
Postpartum
Second
trim
ester
Thirdtrim
ester
Postpartum
Raltegravir
Watts
etal.[10]a
2.35(0.37–5.96)
1.8
(0.3–7.8)
3.0 (0
.3–12.6)
60.6
(21.6–191)
74.8 (11.2–286)
34.8
(10–250)
2.9
(1.2–86)
3.7
(1.1–212)
3.6
(1.1–30.5)
Blonket
al.[9]b
1.4
(0.9–2.2)
1.8
(1.1–2.8)
80.1
(57–112)
56.2 (38.8–81.4)
2.6
(1.9–3.5)
2.5
(1.9–3.4)
Reference
non-pregnant
[38]
2.17
58
7–12
Elvitegravir/cobi
Best[11]a
1.5
(1.1–1.6)
1.5
(0.7–1.7)
1.9
(1.1–2.4)
9.5
(7.8–13)
10.4
(7.7–15.8)
5.6
(4.4–8.4)
3.1
(2.6–4.1)
3.5
(3.1–4.8)
8.9
(7.3–13.4)
Marzoliniet
al.[48]
1.27
1.35
10.5
9.8
2.6
3.7
Schalkwijket
al.[49]
1.2
1.1
10
10.7
4.1
6.7
Reference
non-pregnant
[94]
1.7
6.5
12.9
Dolutegravir
Mulligan
etal.[12]
3.6
(2.6–4.6)
3.5
(2.7–4.2)
4.9
(3.8–6.0)
1.05(0.79–1.50)
1.02
(0.81–1.37)
0.77
(0.57–1.05)
11(8.9–13.1)
12.2 (10.4–15.0)
13.5 (10.6–18.6)
Bollen
[59]c
3.4
(33)
3(41)
1.2
(39)
1.1
(56)
9.9
(50)
14.9
(27)
Waittet
al.[60]b
2.6
(2.0–3.3)
4.1/4.2
1.3
(1.8–1.0)
0.8/1.1
NR
NR
Reference
non-pregnant
[62,95]
3.4
1.0
9.5
aMedian(IQR)
bGeometricmean?
95%
confidence
interval;Waittet
al.,postpartum
only
twoparticipants,actual
values
reported
cGeometricmean?
CV%
NRnotreported,IQ
Rinterquartile
range,
Cmaxmaxim
um
concentration,CL/F
apparentclearance,t �
half-life,CV%
percentagecoefficientofvariation
312 R. Galien et al.
3.1.3 Protein binding
Raltegravir shows a moderate protein binding to albumin
of approximately 76–83% [39]. Because no data are
available on the unbound fraction of raltegravir in pregnant
women, we predicted the unbound fraction of raltegravir
during pregnancy based on known protein binding and
known decreases in serum albumin concentrations during
pregnancy [14, 39]. The predicted unbound fraction, based
on known albumin affinity of raltegravir and a 46%
decrease in serum albumin concentrations during preg-
nancy [14], is decreased by \ 1% [39], which is in line
with the results of a preclinical study in rats where no
Table 3 Hypothetical mechanisms of changes in drug metabolism and disposition during pregnancy in relation to the pharmacokinetics of HIV-
integrase inhibitors
Involved metabolic
pathway or drug
transporter
Involved HIV-integrase inhibitors Hypothetical mechanisms of changes in drug metabolism and disposition
due to increased hormones during pregnancy, and pharmacokinetic
consequences
UGT1A1 Raltegravir
[41, 42]
Dolutegravir
[64, 65]
Cabotegravir
[74]
Bictegravir
[81]
Elvitegravir
[52]
Main metabolizing
route
Main metabolizing
route
Main metabolizing
route
Metabolizing route
equal to CYP3A4
Minor metabolizing
route
Possible induction of UGT1A1 activity during pregnancy [16–18] could lead
to increased CL/F and decreased exposure to involved HIV-integrase
inhibitors
CYP3A4 Elvitegravir
[52]
Cobicistat
[53, 54]
Dolutegravir
[64, 65]
Bictegravir
[81]
Main metabolizing
route
Main metabolizing
route/inhibitor
Some contribution
to metabolization
Metabolizing route
equal to UGT1A1
Induction of CYP3A4 activity during pregnancy [19–22] could lead to
increased CL/F and decreased exposure to involved HIV-integrase
inhibitors
CYP2D6 Cobicistat
[54]
Minor metabolizing
route/inhibitor
Induction of CYP2D6 activity during pregnancy [55, 56] could lead to
increased CL/F and decreased exposure to elvitegravir/cobicistat
UGT1A9 Cabotegravir
[74]
Minor metabolizing
route
Induction of UGT1A9 activity during pregnancy [75] could lead to increased
CL/F and decreased exposure to cabotegravir
P-gp Raltegravir
[35, 36]
Elvitegravir
[84]
Cobicistat
[87]
Dolutegravir
[65]
Cabotegravir
[86]
Substrate
Substrate/inhibitor/
inducer
Inhibitor
Substrate
Substrate
Induction of P-gp activity [35], could lead to increased efflux and decreased
exposure to involved HIV-integrase inhibitors
P-gp inhibition by cobicistat [87] may partially reverse increased efflux of
elvitegravir/cobicistat
BCRP Raltegravir
[88]
Cobicistat
[87]
Dolutegravir
[65]
Cabotegravir
[89]
Substrate
Inhibitor
Substrate
Substrate
Induction of BCRP activity [88] could lead to increased efflux and decreased
exposure to involved HIV-integrase inhibitors
BCRP inhibition by cobicistat [87] may partially reverse increased efflux of
cobicistat
UGT UDP-glucuronosyltransferase, CYP cytochrome P450, P-gp P-glycoprotein, BCRP breast cancer resistance protein, CL/F apparent
clearance
Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy 313
difference in unbound fraction during pregnancy was found
[40]. Based on these predictions, we postulate that protein
binding of raltegravir is not relevantly impacted by preg-
nancy and that changes in total plasma concentrations are
unlikely to be the result of changed protein binding.
3.1.4 Metabolism and Clearance
Raltegravir is primarily metabolized by the UGT1A1
isoenzyme [41, 42]. It has been suggested that UGT1A1
activity is increased during pregnancy, resulting in
increased glucuronidation and inactivation of UGT sub-
strates [16, 17]. This may be attributed to increased pro-
gesterone [16] and cortisol [43] levels during pregnancy.
Furthermore, raltegravir is a P-gp substrate, in which
expression in the liver is increased during pregnancy,
which could lead to increased efflux of raltegravir.
The CL/F of raltegravir was significantly increased by
42% during the third trimester of pregnancy versus post-
partum in the study by Blonk et al. [9], and by 74 and 115%
in the second and third trimesters compared with postpar-
tum in the study by Watts et al. [10] (see also Table 2).
Lower absorption could also be an underlying mechanism
for increased CL/F, however absorption did not seem to be
affected in both studies. The increased CL/F, potentially
through UGT1A1 induction and/or increased P-gp
expression, may have resulted in decreased exposure to
raltegravir, varying from 29% [9] to 50% [10] in the third
trimester compared with postpartum. Although increased
CL/F of raltegravir is observed during pregnancy, it
appears that the half-life (t�) of raltegravir is not affected
(see Table 2), which is in line with an increased V/F
[9, 10].
3.1.5 Clinical Relevance
Lower exposure to raltegravir can be expected during
pregnancy as a result of increased CL/F [9, 10]. There is
accumulating evidence that raltegravir exposure correlates
with treatment outcome. In the QDMRK study (raltegravir
800 mg once-daily dosing), an association was found
between trough concentrations (Ctrough) below a suggested
target concentration of 0.020 mg/L and failure to achieve
an undetectable HIV RNA load [44, 45]. Furthermore,
Garrido et al. [46] found a trend of lower raltegravir Ctrough
related to virological failure when raltegravir was admin-
istered at 400 mg twice daily. One may argue that due to
decreased exposure during pregnancy, patients could be at
risk for virological failure. In the study by Blonk et al. [9],
94% of pregnant women showed a Ctrough above the pre-
defined target of 0.02 mg/L. When compared with histor-
ical controls, this target attainment is comparable with that
observed in non-pregnant, HIV-infected patients receiving
a raltegravir-containing regimen (approximately 86.2%
[45]). In addition, Watts et al. [10] found that despite lower
exposure to raltegravir during pregnancy, observed trough
levels were still comparable with those observed in his-
torical controls. An a priori dose adjustment of raltegravir
to counter the effect of pregnancy on pharmacokinetics is
therefore not deemed necessary. The pharmacokinetics of
the novel 1200 mg once-daily regimen (two new 600 mg
tablets) in pregnant women are unknown. Raltegravir
Ctrough of the 1200 mg once daily regimen were 38% lower
compared with Ctrough of the 400 mg twice-daily regimen
in healthy volunteers [47]. Consequently, it is relevant to
study whether this new once-daily regimen will lead to
Ctrough above the target of 0.02 mg/L [45] during
pregnancy.
3.2 Elvitegravir/Cobicistat
Elvitegravir plasma levels are boosted with cobicistat, a
potent CYP3A4 inhibitor; however, the pharmacokinetics
of elvitegravir in combination with cobicistat have not yet
been extensively evaluated during pregnancy. A confer-
ence report of a prospective study (n = 16 patients in the
second trimester, n = 20 patients in the third trimester, and
n = 15 patients postpartum) by Best [11], as well as case
reports of Marzolini et al. [48] and Schalkwijk et al. [49]
have described the pharmacokinetics of elvitegravir in
HIV-infected pregnant women. In this review, we mainly
focus on the study of Best [11].
3.2.1 Absorption
Both elvitegravir and cobicistat are P-gp substrates,
whereas cobicistat is a P-gp inhibitor; therefore, the effect
of increased intestinal P-gp expression on elvitegravir
absorption in pregnancy is uncertain. Best found that the
elvitegravir Cmax was reduced by 32 and 26%, while the
cobicistat Cmax was reduced by 30 and 36%, in the second
and third trimesters, respectively, compared with postpar-
tum [11]. In this study, elvitegravir Cmax was below the
steady-state mean Cmax (1.7 mg/L) in non-pregnant
patients (see Table 2) [50]. Additionally, case reports
observed no effect on elvitegravir Cmax and reduced
cobicistat Cmax [48, 49] during the third trimester com-
pared with postpartum.
3.2.2 Distribution
V/F was not reported in the conference report of Best
[11] and thefore calculated using derived from the CL/F and
t�. V/F of elvitegravir was decreased during the second
(40.9%) and third trimesters (27.0%) compared with post-
partum. Furthermore, the V/F of cobicistat was increased in
314 R. Galien et al.
this study during the second (51.2%) and third trimesters
(42.9%) compared with postpartum [11].
3.2.3 Protein Binding
Elvitegravir shows extensive protein binding to albumin of
approximately 98–99% [30, 51]; cobicistat also highly
binds to albumin (97–98% bound) [30, 51]. Marzolini et al.
[48] measured the fraction unbound (fu) of elvitegravir and
cobicistat in one patient and found that the fu of elvitegravir
was unchanged (fu = 0.3%) when comparing the third
trimester with postpartum. Moreover, the fu of cobicistat
was minimally increased during the third trimester, with an
fu of 2.1 versus 1.8%. Besides this case report, clinical
studies have not examined the unbound fraction of elvite-
gravir/cobicistat in pregnant women. A clinical study by
Custodio et al. [30] in patients with hepatic impairment
found that the free fraction of both elvitegravir (increased
from 1.15 to 1.22%) and cobicistat (increased from 2.71 to
3.23%) was minimally increased compared with healthy
subjects, indicating a lack of a relevant effect of hepatic
impairment on elvitegravir protein binding [30]. Conse-
quently, limited changes in protein binding of elvitegravir
and cobicistat during pregnancy are expected.
3.2.4 Metabolism and Clearance
As previously stated, elvitegravir is primarily metabolized
by CYP3A4 [52], and its pharmacokinetics are boosted
with cobicistat, a strong CYP3A4 inhibitor, to assure
adequate exposure. During pregnancy, induction of
CYP3A4 is expected, based on in vitro [20] and in vivo
data [21, 22]. This induction may therefore also affect the
pharmacokinetics of elvitegravir, and can be explained by
two mechanisms. First, since elvitegravir is a substrate of
CYP3A4 and the activity of this isoenzyme is induced
during pregnancy, increased biotransformation can be
expected. Second, induction of CYP3A4 during pregnancy
also increases the clearance of cobicistat [53]. As cobicistat
is also a CYP2D6 substrate [54], induction of CYP2D6
during pregnancy [55, 56] may also lead to increased
cobicistat clearance. Variation in cobicistat pharmacoki-
netics in the clinically relevant range is likely to impact the
extent of CYP3A4 inhibition; a study on the pharmacoki-
netics of elvitegravir and cobicistat in healthy volunteers
[57] found that a 33% dose reduction of cobicistat (from
150 to 100 mg) resulted in a decreased exposure to
cobicistat of approximately 50%. This decreased cobicistat
exposure led to decreased elvitegravir exposure of 22%. In
pregnant women, decreased cobicistat exposure of 54 and
57% in the second and third trimesters, respectively, was
also observed [11]. Also in pregnant women, a significantly
increased clearance of elvitegravir (98 and 73%) was
observed in the second and third trimesters, respectively,
compared with postpartum [11] (see Table 2), which
resulted in a relevantly decreased exposure to elvitegravir,
varying from 49 to 42% in the second and third trimesters,
respectively, compared with postpartum [11]. This
decrease in elvitegravir exposure is higher than what was
expected as a result of an approximately 50% reduction in
cobicistat exposure, resulting in 22% lower elvitegravir
exposure in healthy volunteers. Therefore, decreased
elvitegravir exposure in pregnancy is not only explained by
decreased exposure to cobicistat but an additional mecha-
nism may play a role [57]. Lastly, the t� of elvitegravir (-
58% and - 61%) and cobicistat (- 26% and - 36%) were
decreased in pregnant women during the second and third
trimesters, respectively, compared with postpartum (see
Table 2) [11]. These results imply that both decreased
exposure to cobicistat and increased metabolism of
elvitegravir by CYP3A4 may explain the observed highly
decreased exposure to elvitegravir during pregnancy.
3.2.5 Clinical Relevance
In general, decreased exposure to elvitegravir/cobicistat
can be expected in pregnant women as a result of reduced
boosting by cobicistat and/or increased clearance of
elvitegravir [11]. It is known that elvitegravir exposure is
related to antiviral activity in treatment-naive and -expe-
rienced patients [58]. DeJesus et al. [58] found that an
elvitegravir target concentration of 0.13 mg/L was needed
to produce a 90% effective response (EC90), measured as
HIV-RNA viral load after 10 days of treatment with
elvitegravir. In clinical studies on pregnancy, exposure to
elvitegravir appeared to be below this target concentration
of 0.13 mg/L. Best [11] found a median elvitegravir Ctrough
of 0.0249 mg/L (interquartile range [IQR] 0.0173–0.0807)
and 0.0570 mg/L (IQR 0.0147–0.0940) during the second
and third trimesters of pregnancy, respectively. Addition-
ally, the case reports of Marzolini et al. [48] and Schalk-
wijk et al. [49] found a total elvitegravir Ctrough below the
target of elvitegravir (0.018 and 0.06 mg/L, respectively).
The results of these studies imply inadequate exposure to
elvitegravir during pregnancy and hence an increased risk
of virological failure. As a result of this, elvitegravir/co-
bicistat is not recommended in HIV-infected pregnant
women according to perinatal guidelines [7].
3.3 Dolutegravir
The pharmacokinetics of dolutegravir have not been thor-
oughly evaluated during pregnancy. A prospective study by
Mulligan et al. [12] (n = 15 patients in the second trime-
ster, n = 28 patients in the third trimester, and n = 22
patients postpartum), as well as two conference reports of
Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy 315
prospective studies by Bollen [59] (n = 8 patients in the
third trimester, n = 5 patients postpartum) and Waitt et al.
[60] (n = 7 patients in the third trimester and n = 2 post-
partum) have described the pharmacokinetics of dolute-
gravir in HIV-infected pregnant women. The report by
Bollen includes the data from a case reported by Schalk-
wijk et al. [61].
3.3.1 Absorption
As with most HIV-integrase inhibitors, dolutegravir is a
P-gp substrate and therefore absorption may be decreased
due to increased intestinal P-gp expression during preg-
nancy. There was no difference in Tmax during pregnancy
compared with postpartum [12, 59], and Cmax was not
substantially different during pregnancy compared with
postpartum, but was marginally lower. Mulligan et al.
found 25 and 27% lower Cmax in the second and third
trimesters, respectively [12]. Additionally, Bollen observed
a minimally increased Cmax (5%) in the third trimester
compared with postpartum [59], while Waitt et al. [60]
noted a 36% lower Cmax in the third trimester compared
with postpartum. Overall, the Cmax observed in the studies
in pregnancy did not deviate from the Cmax observed in
non-pregnant patients, i.e. 3.4 mg/L, with a variance of
27% [62]. We therefore suggest that pregnancy does not
influence absorption of dolutegravir.
3.3.2 Distribution
V/F was derived from the calculated CL/F and t� in the
paper by Mulligan et al. [12], and from the AUC, dose and
t� in the conference report of Bollen [59]. Furthermore, in
the study by Mulligan et al. [12], V/F was shown to be
increased during the second (11%) and third trimesters
(20%) compared with postpartum. In contrast, Bollen [59]
found that V/F was decreased by 27.5% during the third
trimester compared with postpartum. The mechanism
behind this altered V/F of dolutegravir in pregnancy is still
unclear.
3.3.3 Protein Binding
Dolutegravir is approximately 99% bound to plasma pro-
teins, mainly to albumin [29, 63]. Until now, no studies
have analyzed the unbound fraction of dolutegravir in
pregnant women. To predict an effect, we have extrapo-
lated knowledge from studies in moderate hepatically
impaired patients. A clinical study by Song et al. [29]
found that lower albumin concentrations in patients with
hepatic impairment led to an increased fu of dolutegravir,
from 0.23 to 0.54%. A similar change in the fu of dolute-
gravir may also occur during pregnancy.
3.3.4 Metabolism and Clearance
Dolutegravir is primarily metabolized by UGT1A1
enzymes, and secondarily by CYP3A4, oxidative defluo-
rination and glutathione substitution [64, 65]. As stated
previously, induction of both UGT1A1 activity [16, 17]
and CYP3A4 activity [19–22] may occur during preg-
nancy. While the induction of UGT1A1 activity may be
attributed to increased progesterone [16] and cortisol [43]
levels during pregnancy, many other hormones may induce
expression of CYP3A4 [20, 66, 67]. Furthermore,
increased expression of hepatic P-gp might increase the
efflux, and hence increase the clearance of dolutegravir.
Induction of these pathways may increase CL/F and con-
tribute to a decreased exposure to dolutegravir during
pregnancy.
Increased CL/F is in line with the results from the study
by Mulligan et al. [12], where the CL/F of dolutegravir was
significantly increased by 40% during the third trimester of
pregnancy versus postpartum. In this study, decreased
exposure to dolutegravir was observed, varying from 37%
in the second trimester to 29% in the third trimester com-
pared with postpartum[12]. Waitt et al. also observed a
modest reduction in exposure in the third trimester [60].
However, Bollen [59] did not observe a difference in either
the derived CL/F or in exposure during the third trimester
compared with postpartum. Dolutegravir exposure during
pregnancy was similar (47.6 and 49.2 mg h/L reported by
Mulligan et al. [12], 39.4 mg h/L reported by Waitt et al.
[60], and 42.9 mg h/L reported by Bollen [59], which are
also similar to exposure of non-pregnant adults, i.e. 53.8
and 53.6 mg h/L in two clinical trials [68]). The postpar-
tum exposure reported by Mulligan et al. was high com-
pared with the postpartum exposure reported by Bollen, i.e.
65 versus 44.8 mg h/L [12, 59]. This difference seems to
drive the discrepancy between the presence or absence of a
pregnancy effect. Finally, Mulligan et al. [12] and Bollen
[59] found a decreased t� during pregnancy compared with
postpartum (see Table 2).
3.3.5 Clinical Relevance
Conflicting results have been reported regarding exposure
to dolutegravir during pregnancy. Either a decreased, yet
not clinically relevant, or an unchanged exposure to
dolutegravir was observed during pregnancy [12, 59, 60].
The preliminary results of the pharmacokinetic studies in
pregnant women are promising as, in the studies by Bollen
and Waitt et al., dolutegravir Ctrough in all pregnant women
were above this minimum effective concentration of 0.064
mg/L for treatment-naive patients [69, 70], both during and
after pregnancy. Mulligan et al. reported that the Ctrough
during pregnancy was 11- to 14-fold greater than the EC90
316 R. Galien et al.
of 0.064 mg/L. Despite lower total Ctrough levels during
pregnancy [12, 59], it is probable that pregnancy does not
lead to clinically relevant changes in both exposure and
treatment outcome of dolutegravir. We therefore propose
that it is not necessary to adjust the dose of dolutegravir
during pregnancy in treatment-naive patients. However, a
higher exposure may be necessary in patients with a doc-
umented or clinically suspected resistance against dolute-
gravir or in patients with drug interactions; this can be
reached by doubling the dose of dolutegravir [71]. We do
not know whether adequate exposure is reached in preg-
nant patients in whom doubling the dose of dolutegravir is
necessary due to inadequate exposure to, or resistance with,
the single-dose regimen.
3.4 Cabotegravir and Bictegravir
The pharmacokinetics of cabotegravir have not yet been
evaluated during pregnancy. Injectable cabotegravir is a
long-acting HIV-integrase-inhibiting agent in development
and has the advantage of requiring once monthly or longer
dosing intervals. In an ongoing phase III trial, HIV-infected
naive patients are receiving dolutegravir, abacavir and
lamivudine as induction therapy, followed by cabotegravir
and rilpivirine as oral lead-in, and, finally, intramuscular
injections of long-acting cabotegravir and rilpivirine as
maintenance therapy [72].
The pharmacokinetics of bictegravir have not been
examined during pregnancy. Bictegravir is being investi-
gated in phase III clinical trials in co-formulation with
emtricitabine and tenofovir alafenamide. In this review, we
hypothesize the potential effects of pregnancy on the
pharmacokinetics of cabotegravir and bictegravir.
3.4.1 Cabotegravir
As cabotegravir is a P-gp substrate, absorption of the oral
formulation might be influenced by pregnancy; however,
for the injectable formulation, this is not applicable.
Cabotegravir shows high protein binding of[99% and is
mainly bound to albumin [73]. Parasrampuria et al. [28]
studied the pharmacokinetics of cabotegravir in patients
with severe renal impairment, a patient group in which
hypoalbuminemia can also occur, and found that the fu of
cabotegravir was minimally increased from 0.14 to 0.18%,
and from 0.11 to 0.17%, in patients with severe renal
impairment compared with healthy subjects, at 2 and 24 h
post-dose, respectively. Consequently, we do not expect
clinically relevant changes in the protein binding of
cabotegravir during pregnancy. Cabotegravir is mainly
metabolized through glucuronidation by UGT1A1 and
UGT1A9 [74]. The activity of UGT1A1 [16, 17] and
UGT1A9 [75] may be increased during pregnancy, mainly
due to increased levels of progesterone [16], cortisol [43]
and estradiol [75]. It is known that the clearance of
paracetamol [76–78], also a UGT1A1 and UGT1A9 sub-
strate, was increased in pregnant women compared with
non-pregnant controls, varying from 36% [77] to 58% [76].
Hepatic clearance might also be increased due to increased
expression of hepatic P-gp transporters during pregnancy.
These processes are likely to affect the pharmacokinetics of
cabotegravir and result in reduced exposure.
3.4.2 Clinical Relevance
The place of parenteral cabotegravir in pregnancy is
unknown. One may argue whether this long-acting
injectable agent is appropriate for treating HIV-infected
pregnant women as its long apparent t� can be problematic
if pregnant women need to switch to other combination
antiretroviral therapy (cART); for example, in case of
adverse events. Moreover, it is unknown whether maternal
and fetal safety of cabotegravir can be assured during
pregnancy. We hypothesized whether pregnancy may lead
to clinically relevant reduced exposure to cabotegravir. In
general, decreased exposure to cabotegravir can be
expected during pregnancy, caused by potential increased
clearance. It is known that cabotegravir exposure is related
to antiviral activity. Margolis et al. [79] found that the
median cabotegravir Ctrough was 16 (for 400 mg of
cabotegravir administered intramuscularly once monthly)
to 27 times (for 30 mg of cabotegravir administered orally)
above the defined in vitro protein-adjusted 90% inhibitory
concentration of 0.166 mg/L against wild-type HIV in non-
pregnant HIV-infected patients. This indicates that these
concentrations were adequate for reaching viral suppres-
sion. It is plausible that a decrease of cabotegravir Ctrough
during pregnancy would be similar to paracetamol, i.e. an
approximately two-fold decrease [76–78], where the mar-
gin in a non-pregnant women is a factor of 16 above the
target. A dose adjustment of cabotegravir for pregnant
women might therefore not be necessary but requires
prospective evaluation.
3.4.3 Bictegravir
No information is available on whether bictegravir is a
P-gp substrate, and it is unclear whether pregnancy may
alter the absorption of bictegravir. It is also unclear whe-
ther pregnancy will lead to changes in the V/F of bicte-
gravir. Bictegravir shows very high protein binding of
approximately 99.7% [80]. To hypothesize whether the
predicted fu of bictegravir changes during pregnancy, we
extrapolated data from patients with moderate hepatic
impairment to pregnant women. A study from Zhang [31]
found that the fu of bictegravir was increased in patients
Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy 317
with moderate hepatic impairment (fu = 0.81%) compared
with healthy subjects (fu = 0.61%). In line with these
findings, one might expect a similar change in the fu of
bictegravir during pregnancy, indicating the lack of a rel-
evant effect of pregnancy on bictegravir protein binding.
Bictegravir is mainly metabolized by CYP3A4 and
UGT1A1 in an equal proportion [81]. Both CYP3A4
[19–22] and UGT1A1 activity [16, 17] may be increased
during pregnancy. Both of these processes may therefore
lead to increased CL/F, and hence decreased exposure to
bictegravir during pregnancy.
3.4.4 Clinical Relevance
It is known that bictegravir exposure is related to antiviral
activity. Gallant [82] found that mean bictegravir Ctrough
was 13-fold greater than the defined in vitro protein-ad-
justed 95% inhibitory concentration of 162 ng/mL against
wild-type HIV for bictegravir 50 mg in non-pregnant HIV-
infected patients. We do not expect that pregnancy will
reduce Ctrough 13-fold; pregnancy effects are generally in
the magnitude of a factor two. The most prominent effect
that was observed in pregnancy was a 7.5-fold reduction of
elvitegravir Ctrough, also a CYP3A4 and UGT1A1 sub-
strate, but elvitegravir exposure is also dependent on
boosting by cobicistat, which is likewise reduced during
pregnancy. Therefore, we expect that bictegravir Ctrough
[ 162 ng/mL will likely be reached during pregnancy [11],
however this needs to be assessed prospectively. Further-
more, new studies need to prospectively evaluate the
unbound concentrations of bictegravir during pregnancy to
prove that pregnancy does not relevantly affect bictegravir
protein binding.
4 Discussion and Knowledge Gaps
For absorption, we reported the Cmax and Tmax as surrogate
parameters for the rate of absorption. However, these
parameters are not only affected by absorption rate, volume
of distribution and bioavailability but also by the CL/F of a
drug. One should be aware that a potential change in Cmax
and Tmax during pregnancy does not directly imply changes
in absorption.
For volume of distribution, we reported the Vd/F
derived from non-compartmental analysis of pharmacoki-
netic curves at steady-state (after oral dosing). The reader
should be aware that this parameter also depends on
bioavailability, and changes in Vd/F may not reflect a
change in volume.
4.1 Knowledge Gaps
The ultimate goal of antiretroviral therapy in pregnant
women is the prevention of mother-to-child transmission
(MTCT) of HIV and optimal maternal treatment, for which
adequate exposure is necessary. Unfortunately, the clinical
pharmacokinetics of antiretroviral drugs are generally not
studied in pregnant women during clinical drug develop-
ment. However, after approval, these drugs are also pre-
scribed for pregnant women to prevent MTCT of HIV and
to protect the health of the mother. To better understand the
clinical pharmacokinetics in pregnant women, and quanti-
tatively predict the magnitude of changes in exposure for
new drugs, it is important to accurately chart the mecha-
nisms underlying these changes. More knowledge on this
may further facilitate and guide the development of
effective and safe treatment of HIV-infected pregnant
women.
In this review, we discuss that pregnancy leads, or may
lead, to a reduction in pharmacokinetic exposure to HIV-
integrase inhibitors, which may endanger viral suppression.
Of all HIV-integrase inhibitors, the most experience has
been obtained with raltegravir 400 mg twice daily during
pregnancy, and this is now marked as first-line therapy [7].
Besides raltegravir 400 mg twice daily and elvite-
gravir/cobicistat and dolutegravir 50 mg once daily, there
is limited clinical experience regarding the use of other
HIV-integrase inhibitors during pregnancy. For the new
HIV-integrase inhibitors bictegravir and cabotegravir, it is
very difficult to conclude whether pregnancy leads to a
clinically relevant reduction in exposure, and whether the
safety of the unborn child is assured. Knowledge on the
pharmacokinetics of these drugs in pregnancy is very rel-
evant and can be used to inform perinatal guidelines. To
illustrate this, elvitegravir/cobicistat is not recommended
for pregnant women [7] because of inadequate exposure
during pregnancy [11, 48, 49]. We do not know whether
adequate exposure to, and viral suppression of, raltegravir
1200 mg once daily, dolutegravir 50 mg twice daily, and
bictegravir and cabotegravir can be reached using standard
dosing regimens in pregnant women. In particular, for new
antiretrovirals (cabotegravir and bictegravir) it is important
to determine maternal safety and efficacy during preg-
nancy. One also needs to determine whether these new
antiretrovirals do not lead to congenital abnormalities and
teratogenicity. Because therapy with long-acting injecta-
bles cannot simply be stopped during pregnancy, this issue
is of utmost importance for cabotegravir.
Besides the latter, the knowledge gaps on the mecha-
nisms behind the changes in the pharmacokinetics of HIV-
integrase inhibitors during pregnancy need to be studied to
optimize antiretroviral treatment during pregnancy.
318 R. Galien et al.
Increased progesterone levels during pregnancy may
induce UGT1A1-mediated metabolism [16, 83]; UGT1A1
plays a role in the metabolism of all HIV-integrase inhi-
bitors. Induced UGT1A1 expression leading to increased
intrinsic clearance may explain the observed decreased
exposure to, for example, raltegravir during pregnancy.
However, we do not know to what degree UGT1A1
induction explains variability in the pharmacokinetics of
HIV-integrase inhibitors. Analyzing metabolites in preg-
nancy might help to elucidate this knowledge gap.
Furthermore, we do not know whether pregnancy-re-
lated CYP3A4 induction plays a major role in increased
clearance and decreased exposure to HIV-integrase inhi-
bitors. Since elvitegravir, bictegravir and dolutegravir are
all partly converted by CYP3A4, this may be an important
factor in altered exposure of these drugs in pregnancy.
Determination of metabolites could help to understand the
role of altered CYP3A4 metabolism in pregnancy.
The extent to which altered drug transporter activity in
pregnancy influences the pharmacokinetics of HIV-inte-
grase inhibitors in pregnancy is currently unclear. Potential
effects of changes in transporter expression are presented
in Table 3. Since raltegravir [35, 36], elvitegravir/cobicis-
tat [84], dolutegravir [85] and cabotegravir [86] are all
substrates of P-gp (for bictegravir this information was not
available), one may expect that increased expression of
P-gp during pregnancy may lead to decreased absorption
and increased hepatic efflux. Elvitegravir disposition may
be subject to a more complex mechanism because of co-
administration of cobicistat. Increased elvitegravir efflux
during pregnancy may potentially be partially reversed by
cobicistat, which inhibits P-gp activity [87]. However,
should relevant P-gp inhibition occur, this did not affect
CL/F as we saw a marked increase in this parameter of
elvitegravir during pregnancy [11]. Additionally, since
raltegravir [88], cobicistat [87], dolutegravir [65] and
cabotegravir [89] are all substrates of breast cancer resis-
tance protein (BCRP), it can be expected that increased
expression of BCRP in pregnant women may also lead to
increased efflux. Generally, increased efflux may result in
decreased exposure to HIV-integrase inhibitors during
pregnancy, and hence an increased risk of viral MTCT.
However, changes in drug transporter activity and expres-
sion during pregnancy, and their impact on exposure to
HIV-integrase inhibitors, have not yet been examined in
HIV-infected pregnant women and therefore remains a
knowledge gap.
The relationship between altered hormone levels in
pregnancy and induction/inhibition of enzymes and trans-
porters, as well as other physiological changes taking place
during pregnancy, has not been studied for HIV-integrase
inhibitors. Population pharmacokinetic analysis could help
to find relevant covariates (such as hormonal
concentrations during pregnancy) influencing the pharma-
cokinetics of these drugs in pregnancy.
A knowledge gap exists on how enterohepatic circula-
tion of HIV-integrase inhibitors changes during pregnancy.
There is evidence that raltegravir [90] and dolutegravir [64]
undergo enterohepatic circulation. One may expect that a
possibly higher degree of enterohepatic circulation during
pregnancy, caused by increased UGT1A1 activity,
increased glucuronidation, subsequent active biliary
excretion of the deconjugated glucuronide, and reabsorp-
tion, may change the pharmacokinetics of HIV-integrase
inhibitors. This mechanism has not been studied in detail in
pregnancy.
Furthermore, very little information is available on the
unbound concentrations of HIV-integrase inhibitors during
pregnancy. This may provide difficulty in assessing the
relation between exposure and response during pregnancy
(virologic response or toxicity), as, in most cases, only the
unbound drug is pharmacologically active. Generally,
changes in protein binding are not clinically relevant as the
unbound concentration remains unchanged [91]. It should
be noted that if only total plasma concentrations are
assessed, decreased plasma protein binding may be incor-
rectly interpreted as increased clearance due to the
decreased total concentration, despite unchanged unbound
concentrations. Consequently, it is key to measure the
unbound concentrations of HIV-integrase inhibitors during
pregnancy [92]. More information on this will help us to
evaluate the clinical relevance of a potential decrease in
total exposure during pregnancy.
Lastly, another important knowledge gap exists on the
safety of the unborn child during therapy with HIV-inte-
grase inhibitors in pregnant women. Information should be
collected to indicate for which new HIV-integrase inhibi-
tors adequate safety of the unborn child can be assured
during pregnancy. For example, by collecting safety
information of HIV-infected pregnant women in an inter-
national registry, such as the Antiretroviral Pregnancy
Registry (APRegistry) [93], one will gain more insight into
the safety of both the mother and the unborn child during
pregnancy.
5 Conclusions
Pregnancy decreases exposure to raltegravir and elvite-
gravir. Exposure to dolutegravir may also be decreased in
pregnancy, although conflicting results on this issue have
been reported in the literature. Despite potential decreased
exposure, Ctrough above the target concentration is reached
with raltegravir 400 mg twice daily and dolutegravir 50 mg
once daily during pregnancy. Elvitegravir Ctrough is below
the target concentration in most women during pregnancy,
Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy 319
indicating possible inadequate exposure. It is unknown
whether adequate exposure of cabotegravir, bictegravir,
raltegravir 1200 mg once daily, and dolutegravir 50 mg
twice daily is reached during pregnancy, but decreased
exposure is expected; further studies are required to
prospectively assess the clinical relevance and extent of
decreased exposure. Until such time as these new studies
have been performed, it is recommended that these newHIV-
integrase inhibitors not be used during pregnancy. If preg-
nant women are already using the new HIV-integrase inhi-
bitors, we recommend performing therapeutic drug
monitoring of these agents, if available, andmonitoring viral
load in HIV-infected pregnant women using this class of
drugs. For raltegravir, elvitegravir and dolutegravir, target
concentrations can be defined and have been reported in this
paper under the clinical relevance section of each drug.
Furthermore, knowledge gaps on themechanisms behind the
changes in the pharmacokinetics of HIV-integrase inhibitors
during pregnancy still exist. Further studies are required to
unravel the mechanisms behind the changes in the pharma-
cokinetics of HIV-integrase inhibitors during pregnancy.
More information on these mechanisms will also help us to
predict changes in the pharmacokinetics and safety of new
HIV-integrase inhibitors during pregnancy. More knowl-
edge on changes in the pharmacokinetics of these drugs can
be used for recommendations in perinatal guidelines, which
helps us to optimize pharmacotherapy with HIV-integrase
inhibitors in pregnant women.
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the preparation
of this review.
Conflict of interest Angela Colbers and David Burger run the
PANNA network, which is supported by the European AIDS Treat-
ment Network, The European Commission, DG Research, Sixth
Framework Program, contract LSHP-CT-2006-037570, Bristol-Myers
Squibb, Merck Sharp & Dohme Corp, Gilead Sciences, ViiV
Healthcare and Janssen Pharmaceuticals NV. Ruben van der Galien,
Rob ter Heine, Rick Greupink, Stein J. Schalkwijk, and Antonius E.
van Herwaarden have no conflicts of interest to declare.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
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